The present invention relates to pharmaceutical compositions comprising Cyclosporin as active ingredient. The present invention also relates to novel alcohol free, free flowing, clear and transparent compositions comprising Cyclosporin as an active ingredient. The novel compositions are characterised in having increased bio-availability when the drug is formulated in a solubilised system and also amenable to convenient commercial production.
Cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first of the Cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as Cyclosporin A and commercially available under several brands. Ciclosporin is the Cyclosporin of formula A. 
whereinxe2x80x94MeBmtxe2x80x94represents the N-Methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L) threonyl residue of formula B. 
in which xe2x80x94xxe2x80x94yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 (trans).
Naturally occurring and semi-synthetic Cyclosporins, their classification, nomenclature etc. are known [c.f Traber et al. 1, Helv. Chim Acta. 60, 1247-1255 (1977): Traber et al. 2, Helv. Chim. Acta. (65 no. 162, 1655-1667 (1982)); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240(1980); and von Wart -burg et al., Progress in allergy , 38,28-45(1986)]. U.S. Pat. Nos 4,108,985, 4,210,581 and 4,220,641; European Patent Publication Nos. 0034567 and 0056782; International Patent Publication no. WO 86/02080; Wenger 1, Transp. Proc. 15, Suppl. 1; 2230 (1983); Wenger 2, Angew. Chem. Int. Ed., 24,77 (1985); and Wenger 3, Progress in Chemistry of Organic natural
Products 50, 123(1986). Other Cyclosporins are known from U.S. Pat. Nos. 4,639,434; 4,703,033; 4,764,503, 4,885,276; 5,116,816; 5,122,511; 5,525,590; 5,643,870 and 5,767,069.
So far the primary area of clinical investigation for cyclosporins and in particular, Ciclosporin has been as an immunosuppressive agent, in particular in relation to its application to recipients of organ transplants, e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, bone-marrow, skin and corneal transplants and, in particular, allogenic organ transplants. In this field Cyclosporins, in particular ciclosporins have achieved a remarkable success. Among all the Cyclosporins, Cyclosporin A (also known as Cyclosporine or Ciclosporin) has established its utility in the area of organ transplant and therapy of autoimmune diseases.
At the same time, applicability of Cyclosporins including Ciclosporin to various autoimmune diseases and to inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are wide-spread in the literature. Specific auto-immune diseases for which Cyclosporin and Ciclosporin therapy has been proposed or applied include, autoimmune hematological disorder (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia), systemic lupus erythematosus, poly-chondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn""s disease) endocrine opthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type 1), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthirits and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).
Further areas of investigation for cyclosporins include potential applicability as an anti-parasitic, in particular anti-protozoal agent, with possible uses suggested including treatment of malaria, coccidiomycosis and schistosomiasis and, yet more recently, use as an agent for reversing or abrogating anti-neoplastic agent resistance in tumours and the like.
Although Cyclosporin A is the most widely used amongst all the immunosuppresants available so far, it suffers from a serious drawback of poor bio-availability. Cyclosporin blood levels have to be maintained within a specified range to achieve the effective therapy. The required range varies according to the clinical status of the patient.
Because of poor and variable bioavailability daily dosages needed to achieve the desired blood levels need to be varied considerably in the existing dosage forms of Cyclosporin and a concomitant monitoring of blood levels is essential. This adds an additional cost to the therapy.
In order to improve the bio-availibility several attempts have been made to improve formulations of Cyclosporin. The oral dosage forms known in the market (i.e. those employing ethanol, olive oil as carrier medium in conjunction with Labrafil as surfactant (see U.S. Pat. No. 4,388,307) are unpleasant tasting galenic forms. The bio-availability levels using these dosage forms are low and exhibit wide inter-and intra-individual variations. Such dosage forms provide an average absolute bioavailability of ca 30%. Reported variation in bio-availability between subjects varies between a few percent for some patients to as much as 90% or more for others. Also a marked change in bio-availability for individuals with time is frequently observed.
U.S. Pat. No. 4,388,307 also describes a drink solution containing Cyclosporin in a base of Labrafil, Miglyol, Ethanol, Corn/olive oil. However, such preparation suffered from the draw back that it can be presented only as a liquid for dilution in drinking water/fluid before use, otherwise it is very difficult to give an accurate dose. Bioavailability levels achieved using the systems is very low and exhibits wide variations between individuals, individual patient type and even for single individuals at different times during the course of therapy.
Han Gua Patent (Chinese Patent No. 94191895.5) explains the active compound of Cyclosporin, fatty acid sugar ester and diluent carrier having good bio-availability. However, this compound suffers from the drawback that diluent degrades due to hygroscopicity of sugar ester and the stability is not of desired standards, (See also Pharmaceutical Research, Volume 6, No. 11, 1989, P958, xe2x80x9cSolid Surfactant Solution of active Ingredients in Sugar Esterxe2x80x9d and International Journal of Pharmaceutics, Vol. 92, 1993, P197,xe2x80x9cApplication of sucrose laurate a new pharmaceutical excipient, in Peroral formulation of Cyclosporin Axe2x80x9d).
Chinese Patent 9419189.5 having equivalent EP 0702562 describes a powder dosage form of Cycloproin possessing comparatively higher stability and to some extent bio-availability when compared to the earlier formulations. This art describes adsorption of Cyclosporin A with appropriate solvents onto an adsorbent along with a nonionic hydrophillic surfactant. The final product does not contain the solvent as this evaporates during the process of manufacturing. Thus this product does not suffer from the disadvantage arising out of solvent evaporation during shelf life and hence stability problems. The various pharmaceutical surfactants, polyhydric alcohols and solvents are well known to the art. The adsorbent used is Colloidal Silicon Dioxide. The blood level arising out of such product have been compared with the standard formulations as per U.S. Pat. No. 4,388,307 with significant improvement in bioavailability. However, if compared with the micro-emulsion based formulations these formulations do not show any advantage as the drug is adsorbed on solid surface and needs an additional process of dissolution prior to become bioavailable.
The effect of sucrose laurate-on the gastrointestinal absorption of Cyclosporine is also described (Lerk-PC; Sucker-H, International Journal of Pharmaceutics; 1993; 92; (May 3); 197-202). The evaluation of the dosage form containing sucrose Laurate was found to enhance the in vitro absorption of Cyclosporine when normal epithelial tissue and Peyer""s patch tissue of guinea pigs were used. Compared to the commercially available drinking solution, absorption was raised by a factor of 10. Excess amount of surfactant reduced drug absorption. Despite large excess of Sucrose laurate, the absorption of Cyclosporin was still superior to the drinking solution. Choleic acid was also found to increase absorption by a factor of 5-6. A comparison of the absorption between normal epithelial and Peyer""s patch tissues indicated that the absorption by endocytosis does not contribute significantly to the overall absorption of Cyclosporin. It was concluded that preliminary formulation experiments showed that a solid oral dosage form of Cyclosporin could be made using sucrose laurate as an excipient.
Abdallah-H Y; Mayersohn-M. Pharmaceutical Research; 1991;8(Apr);518-522 reported several formulations of Cyclosporin were prepared and examined in vitro and in dogs A tablet formulation was then selected for comparison with the commercial oil solution placed in a soft gelatin capsule in a randomized crossover study in dogs. Compared with an intravenous dose of the drug, absolute bioavailability was 46+11.1 and 45+9.9% for the capsules and tablets, respectively. Maximum concentration, time to reach maximum concentration and mean absorption time were not significantly different between the 2 formulations. It was concluded that the tablet formulation of Cyclosporin is equivalent in dogs to the commercial dosage form packed into soft gelatin capsules.
U.S. Pat. No. 5,051,402 describes that Cyclosporin may be rendered more soluble by the concomitant administration of xcex1-Cyclodextrin, either separately, but essentially simultaneously or, preferably, in admixture.
U.S. Pat. No. 4,990,337 describes a formulation comprising a Cyclosporin in admixture with at least one mono or diglyceride of a C6-C10 fatty acid sufficient to dissolve the Cyclosporin. The resulting solution can then easily be emulsified in water or an aqueous fluid.
Freeze dried liposome mixture containing Cyclosporin has been described in U.S. Pat. No. 4,963,362. This invention provides a freeze-dried potential liposome mixture having an amphipathic lipid and a Cyclosporin or derivative thereof for use in possible liposome delivery of Cyclosporin into cells. A method to-produce the freeze-dried mixture is also disclosed. When reconstituted to yield liposomes in an aqueous medium, substantially all of the Cyclosporin present in the freeze-dried mixture is encapsulated in the liposomes.
Other galenic improvements in Cyclosporin emulsion formulations recorded in prior art are the use of tocopherol derivatives (EP 0724452), tocopheryl polyethyleme glycol carboxylic acid ester (EP 0712631), dimethylisosorbide (EP 0711550, EP 0650721), alkylene polyether or polyester (WO 9423733), emulsion compositions (EP 0694308), anhydromannitol oleylether, lactoglyceride, citroglycerides (EP 656212), phosphatidyl ethanolamine (EP 0651995), as surfactants and stabilizers etc.
Three Patent Applications namely European Patent App. No. 94110184.2, 95117171.9 and PCT/EP95/04187 describe the use of Dimethylisosorbide as a co-surfactant or a hydrophillic phase along with other ingredients to enhance the absorption of Cyclosporin.
One of the most significant attempt to improve bio-availability of Cyclosporin from its dosage form is the described in U.S. Pat. No. 5,342,625. This art describes use of microemulsion pre-concentrate consisting of a three phase systems i.e. (1) a hydrophilic phase component (2) a lipophilic phase component and (3) a surfactant. Such composition has alcohol as an essential ingredient. Such composition upon dilution with water provides an oil-in-water microemulsion with an average particle size of less than 1000 xc3x85. Such an enhanced surface area results in increased bio-availability of Cyclosporin when compared with conventional dosage forms. A comparison of bio-availability from micro-emulsion dosage form (Composition I from U.S. Pat. No. 5,342,625) with the conventional ethanol-oil based dosage form (composition from U.S. Pat. No. 5,342,625), earlier reported in U.S. Pat. No. 4,388,307) has been performed in healthy human volunteers and reported in U.S. Pat. No. 5,342, 625. Bio-availability level of 149.0% (xc2x148) is recorded for composition I as compared to composition X (for which bio-availability achieved is set as 100%). The mean AUC levels from composition I were 40% higher when compared to those from composition X but still had a high variation of 20%.
Some of the later U.S. Pat. Nos. 5,866,159, 5,916,589, 5,962,014, 5,962,017. 6,007,840 and 6,024,978 also pertain to oil-in-water microemulsion compositions having particle size less than 2000 xc3x85.
U.S. Pat. No. 5,977,066 discloses oral compositions using monoglycerides, diglycerides and triglycerides alongwith castor oil derivatives. Compositions of the present invention do not contain fatty materials like mono-,di-, or triglycerides.
U.S. Pat. No. 6,022,852 discloses the use of tocopherol polyethylene glycol 1000 succinate for formulating Cyclosporin A.
Hong et al. In U.S. Pat. No. 6,028,067 disclose the use of lipophilic solvent chosen from an alkyl ester of polycarboxylic acid and a carboxylic acid ester of polyols, alongwith an oil; and a surfactant to form microemulsion preconcentrate of cyclosporin A. Such lipophilic solvents are not present in the present invention.
Sherman Bernard Charles (WO9848779) claim an emulsion preconcentrate comprising a cyclosporin dissolved in a solvent system comprising acetylated monoglycerides, and a surfactant.
Robert Floc""h et al. In U.S. Pat. No. 5,827,822 disclosed aqueous suspension of amorphous Cyclosporin nanoparticles wherein at least 50 percent of the drug is present as particles of less than about 1 xcexcm.
Alcohol is an essential part of most of the marketed compositions as is evident from the products available in the market (Sandimun [U.S. Pat. No. 4,388,307] and Neoral [U.S. Pat. No. 5,342, 625]) both of which contain Alcohol. Such compositions suffer from severe drawback of instability due to evaporation of a low boiling solvent like Alcohol. This is particularly true as the products are used in home environment, which cannot be precisely controlled with respect to temperature. Although very expensive and cumbersome technology (such as cold formed Aluminium/ Aluminium Blister packs) is adopted to protect these products, yet the problem of instability is not completely solved. The stability problems are evident from strict storage conditions and usage requirements as declared either on the labels or package inserts of commercial products Sandimun, and Neoral drink solutions and capsules. Some of the examples are:
1. There is a requirement of storage of product below 30xc2x0 C. at the same time refrigeration is prohibited. This means that a patient using this product in a tropical country need to have an air-conditioned home environment. This is not only a limiting factor in use of this product but sometimes in economically backward countries it may not be possible that every person using the product has an air-conditioned storage area. Sometimes factors like prolong electricity failure and mechanical and electrical defects in air-conditioning system can cause instability problems to these products rendering them unstable for use.
2. There is also an a statement in Packing insert of Sandimun and Neoral drink solutions that xe2x80x9cSandimun Neoral solution should be used within 2 months of opening the bottle and be stored between 15xc2x0 and 30xc2x0 C., preferably not below 20xc2x0 C. for prolonged periods, as it contains oily components of natural origin which tend to solidify at low temperatures. A jelly-like formation may occur below 20xc2x0 C., which is however reversible at temperatures up to 30xc2x0 C. Minor flakes or a slight sediment may still be observed. These phenomena do not affect the efficacy and safety of the product, and the dosing by means of the pipette remains accurate.xe2x80x9d indicating instability problems.
U.S. Pat. No. 5,639,724 discloses pharmaceutical compositions comprising Cyclosporin, transesterification product of a natural vegetable oil with glycerol which is exemplified in the specification as MAISINE (transesterification product of corn oil and glycerol) which is an essential component of the compositions. The cyclosporin must be mixed with a transesterfication product of a natural vegetable oil with glycerol. These compositions are not useful as drink solutions because of formation of jelly like lumps, since the transesterfication product is a jelly like substance at room temperature. Such composition also preferably require the use of alcohol. This compositions compares its bioavailability with that of older and inferior compositions based on U.S. Pat. No. 4,388,307 and does not compare bioavailability with a more recently marketed compositions (NEORAL) as defined in U.S. Pat. No. 5,342,625. U.S. Pat. No. 5,639,724 discloses the use of Labrafil as a preferred ingredient to be added to the composition of Cyclosporin and MAISINE for a drink solution. However, this patent does not address the problem of flake like substances formed by the presence of MAISINE even though Labrafil has been added to the composition.
Any person skilled in the art attempting to make compositions without the use of alcohol and without careful and extensive experimentation and study of desired chemicals to be added to Cyclosporin will end with compositions which are highly viscous and which tend to solidify at normal room temperature conditions. Such compositions are undesirable not only due to physical instability but also that they cannot be formulated as liquids whose dose can be measured exactly under normal conditions.
The major consideration here is the accurate measurement of dose in Cyclosporin which is an essential feature because of the narrow therapeutic condition of the drug i.e. below threshold the organ rejection occurs and above a particular level the drug causes severe toxic reactions.
All the earlier approaches to enhance the bioavailability of Cyclosporin were towards making the drug in a emulsified form (U.S. Pat. No. 4,388,307) or substantially increasing the surface area by converting into microemulsion (U.S. Pat. No. 5,342,625).
Our attempt has been to affect solubilisation of cyclosporin using the concept of surfactant and co-surfactant. In the U.S. Pat. Nos. 5,342,625 and 5,741,512 a xe2x80x9clipophilic componentxe2x80x9d forms an essential part of the composition. This lipophilic component has been defined in the said patents as solvents which are devoid or substantially devoid of surfactant function and non-miscible with the selected hydrophilic phase. The compositions of the present invention are substantially devoid of such xe2x80x9clipophilic componentsxe2x80x9d and hence also devoid of the defects associated with such fatty materials. Compositions according to this invention may be formulated for oral administration including but not limited to drink solutions or formulated as hard or soft gelatin capsules. The capsules may be gelatin or cellulose capsules or two piece hard shell capsules. Drink solution formulations may be diluted with water or aqueous medium and the lipophilic Cyclosporin drug is maintained in a solubilized state, hence making the drug bioavailable in therapeutic concentrations.
Oral solution concentrates are to be diluted prior to intake and are used as start up therapies. These dosage forms provide more flexibility in dosage adjustments to achieve the optimum therapeutic concentrations as desired by the physicians. The second type of dosage forms are unit dosage forms for example capsules, generally soft or hard gelatin capsules or cellulose capsules or two piece hard shell capsules.
In accordance with the present invention there is described a homogenous substantially alcohol free, composition of Cyclosporin which comprises a Cyclosporin in a hydrophillic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range:
Cyclosporin A: 1-25% w/w
Propylene Glycol: 2.5-70% w/w
Esters of propylene glycol with C4 to C12 fatty acids: 2.5-70% w/w
Polyoxyethylene hydrogenated Castor oils: 2.5-70% w/w